In the United States a person is diagnosed with cancer every 23 seconds. In men, prostate cancer (PRCA) is the most frequently diagnosed of these cancers. Despite the huge incidences of cancer there are few models of human cancer that progress from a benign human tissue into malignant and metastatic tissues utilizing compounds normally found in body. The long term objective of this project is to develop better methods for the prevention and treatment of prostate cancer. Typically, PRCA arises in epithelial tissue and initially responds to androgen ablation therapy. The established paradigm to explain the role of androgen-signaling in the PRCA-progression posits that PRCA is mediated by sex hormone signal transduction in prostatic epithelial cells. This finding has led to the theory that aberrant androgen receptor (AR)-signaling in prostatic epithelial cells is an important early event in the development of prostate cancer. However, recent studies suggest that events in non-epithelial tissues may also contribute to the oncogenic process. To the end of understanding the true mechanisms of androgen-signaling and induction of PRCA-progression, we have developed two novel tissue recombination models that recapitulate key genetic and epigenetic events and processes found in human PRCA. Our data show that in contrast to the established paradigm of epithelial AR-mediated PRCA-progression, AR-signaling in stromal cells is the critical androgen regulated event in the earliest stages of PRCA-progression. Therefore, the central hypothesis of this proposal is that human PRCA is initiated by inappropriate AR activity in stroma. Utilizing these tissue recombinant models we will determine the mechanism of androgen action in PRCA-progression and determine the downstream mechanism by which AR mediates malignant transformation of the epithelium. These experiments will provide key insight into the prevention of human PRCA and lead to a better understanding of the mechanisms of androgen action in human prostate carcinogenesis.